Gab2促进髓源性抑制细胞（MDSCs）功能介导肝癌发展的机制探究

我们的研究成果揭示敲除Gab2改善脂肪肝症状、干扰IL-6信号通路抑制肝癌发生，但其介导肝癌进程的机制不明确。我们前期研究发现，小鼠肝脏过表达Gab2促进肝癌发展及IL-6分泌，增加髓源性抑制细胞（MDSCs）标志物及血管生成因子合成，抑制免疫激活因子分泌。文献调查显示IL-6可诱导MDSCs促血管生成和免疫抑制功能，这两个功能是肝癌发生的重要环节。因此我们猜测Gab2可能通过IL-6介导MDSCs功能调控肝癌发展。本课题将从动物、细胞及临床样本层次，运用过表达Gab2小鼠、慢病毒干扰、MDSCs及T细胞分离等方法，探究Gab2对肝癌形成中MDSCs扩增和功能的影响；明确IL-6在Gab2调控MDSCs特性中的作用；体外阐明Gab2促进MDSCs功能调控肝癌进程的分子机制；揭示临床上Gab2、IL-6和MDSCs的相关性。本研究从新角度探究Gab2调控肝癌的作用机理，为肝癌防治提供新思路。

Our previous research revealed that deletion of Gab2 ameliorates symptoms of fatty liver, and inhibits the development of primary liver cancer by interfering IL-6 signaling networks. However, the underlying mechanism of Gab2-mediated the progression of Hepatic carcinoma remains unclear. Our previous studies found that mouse liver-specific Gab2 overexpression promoted the development of Hepatic carcinoma, tumor growth, and IL-6 secretion, enhanced the expression of MDSCs-related proliferative and activated genes (S100A8, S100A9, and Arg-1; Gr-1 positive staining cells number) and tumor angiogenesis factor (VEGF), accompanied by inhibiting the secretion of immunosuppressive factors (IL-4 and IL-13) that acted as the activator of T cells. It is confirmed that IL-6 can induce the function of MDSCs-mediated immunosuppression and angiogenesis, which are the important developing link of liver cancer. Hereby, we suspect that Gab2 possibly regulates the progression of Hepatic carcinoma through affecting IL-6-mediated the functional change of MDSCs. In the present project, we will perform in vivo and in vitro experiments applying liver-specific Gab2 overexpression transgenic mice, lentivirus interference and mouse MDSCs and T cells isolation bio-technology, to explore the effects of Gab2 on accumulation and function of MDSCs in the formation of Hepatic carcinoma, clear the role of IL-6 in the cause of Gab2-mediated the properties changes of MDSCs, illustrate the regulation mechanism of Gab2 on the functional changes of MDSCs in the progression of liver cancer in vitro, and reveal the clinic correlation between Gab2, IL-6, and MDSCs in liver cancer patients. This study will shed a new perspective to explore the underlying mechanism of Gab2 on the development of Hepatic carcinoma, and provide a novel insight for the prevention and treatment of Hepatic carcinoma in clinically.